Dual mode of action soluble guanylate cyclase activators and phosphodiesterase inhibitors and uses thereof

Abstract

The present invention relates to compounds of formula Ior pharmaceutically acceptable salt, solvate or hydrate thereof, whereinat least one of R1, R2, R3, R4, or R5 independently of each other comprises at least one ONO2 or ONO moiety;R1 is C1-C3alkyl optionally substituted with F, C3-C6cycloalkyl, C1-C3alkoxy, ONO, ONO2;R2 is H, C1-C3alkyl optionally substituted with OH, ONO, ONO2; C(O)OH, C(O)OC1-C3alkyl, CHO, CN, C(O)N(R6)OR7, CR8═N—OR9, CR8═N—NR10R11, CR8═NR12, CR8═N—ONO2, C1-C3alkoxy; C1-C3alkylene-Y, wherein Y is ONO, ONO2, C(O)OH, C(O)OC1-C3alkyl, CHO, CN, OH, OC(O)H, OC(O)—C1-C3alkyl, C(O)N(R6)OR7, OC1-C3alkylene-C(O)OH, OC1-C3alkylene-C(O)OC1-C3alkyl, OC1-C3alkylene-C(O)N(R6)OR7, S(O0-2)C1-C3alkyl, CR8═N—OR9, CR8═N—NR10R11, CR8═NR12 or CR8═N—ONO2;R3 is C1-C4alkyl optionally substituted with F, OH, ONO, ONO2, C1-C3alkoxy, C3-C6cycloalkyl; C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkynyl;R4 is C1-C6alkyl optionally substituted with C3-C6cycloalkyl, C1-C6alkoxy, F, ONO, ONO2; C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl;R5 is H, SO2NR13R14, NHSO2NR13R14;R6 is H or C1-C3alkyl;R7 is H, C1-C3alkyl, C1-C3alkoxy, C1-C3alkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C1-C3alkyl, F;R8 is H, CH3 or C2H5;R9 is H, C1-C3alkyl optionally substituted with OH, ONO, ONO2, CN, COOH, COOC1-C3alkyl, C1-C3alkoxy, OC(O)H, OC(O)—C1-C3alkyl, C(O)N(R6)OR7, OC1-C3alkylene-C(O)OH, OC1-C3alkylene-C(O)OC1-C3alkyl, OC1-C3alkylene-C(O)N(R6)OR7, S(O0-2)C1-C3alkyl;R10 and R11 are each independently H, C1-C3alkyl optionally substituted with OH, ONO, ONO2, CN, COOH, COOC1-C3, C1-C3alkoxy, OC(O)H, OC(O)—C1-C3alkyl, C(O)N(R6)OR7, OC1-C3alkylene-C(O)OH, OC1-C3alkylene-C(O)OC1-C3alkyl, OC1-C3alkylene-C(O)N(R6)OR7, S(O0-2)C1-C3alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C1-C3 alkyl;R12 is C1-C3 alkyl optionally substituted with OH, ONO, ONO2, CN, COOH, COOC1-C3alkyl, C1-C3alkoxy, OC(O)H, OC(O)—C1-C3alkyl, C(O)N(R6)OR7, OC1-C3alkylene-C(O)OH, OC1-C3alkylene-C(O)OC1-C3alkyl, OC1-C3alkylene-C(O)N(R6)OR7, S(O0-2)C1-C3alkyl;R13 and R14 are each independently H or C1-C6alkyl optionally substituted with F, OH, ONO, ONO2, COOH, C1-C3alkoxy, C3-C6cycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R15;R15 is C1-C6alkyl optionally substituted with halogen, OH, ONO, ONO2, C1-C3alkoxy, C1-C3haloalkoxy, COOR16, NR17R18, C═NR19, or with a tetrazole moiety which is optionally substituted with C1-C3alkyl; or a heteroaryl ring which is optionally substituted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen;R16 is H, or C1-C4alkyl optionally substituted with F, OH, ONO, ONO2, NR17R18, or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitrogen, and wherein preferably said heteroaryl ring is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole, wherein nitrogen atom is directly bound to C1-C4 alkyl;R17 and R18 are each independently H or C1-C4alkyl optionally substituted with ONO, ONO2;R19 is C1-C4alkyl optionally substituted with F, ONO, ONO2; C3-C6cycloalkyl;and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.

The invention claimed is: 
     
       1. A compound of formula I 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein 
         at least one of R 1 , R 2 , R 3 , R 4 , or R 5  independently of each other comprises at least one ONO 2  or ONO moiety; 
         R 1  is C 1 -C 3 alkyl optionally substituted with F, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, ONO or ONO 2 ; 
         R 2  is H, C 1 -C 3 alkyl optionally substituted with OH, ONO or ONO 2 ; C(O)OH, C(O)OC 1 -C 3 alkyl, CHO, CN, C(O)N(R 6 )OR 7 , CR 8 ═N—OR 9 , CR 8 ═N—NR 10 R 11 , CR 8 ═NR 12 , CR 8 ═N—ONO 2 , C 1 -C 3 alkoxy or C 1 -C 3 alkylene-Y, wherein Y is ONO, ONO 2 , C(O)OH, C(O)OC 1 -C 3 alkyl, CHO, CN, OH, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , S(O 0-2 )C 1 -C 3 alkyl, CR 8 ═N—OR 9 , CR 8 ═N—NR 10 R 11 , CR 8 ═NR 12  or CR 8 ═N—ONO 2 ; 
         R 3  is C 1 -C 4 alkyl optionally substituted with F, OH, ONO, ONO 2 , C 1 -C 3 alkoxy or C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; 
         R 4  is C 1 -C 6 alkyl optionally substituted with C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, F, ONO or ONO 2 ; C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl; 
         R 5  is H, SO 2 NR 13 R 14  or NHSO 2 NR 13 R 14 ; 
         R 6  is H or C 1 -C 3 alkyl; 
         R 7  is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C 1 -C 3 alkyl or F; 
         R 8  is H, CH 3  or C 2 H 5 ; 
         R 9  is H, C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, COOC 1 -C 3 alkyl, C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7  or S(O 0-2 )C 1 -C 3 alkyl; 
         R 10  and R 11  are each independently H or C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, COOC 1 -C 3 , C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7  or S(O 0-2 )C 1 -C 3 alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with C 1 -C 3  alkyl; 
         R 12  is C 1 -C 3  alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, COOC 1 -C 3 alkyl, C 1 -C 3 alkoxy, OC(O)H, OC(O)—C 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)OC 1 -C 3 alkyl, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7  or S(O 0-2 )C 1 -C 3 alkyl; 
         R 13  and R 14  are each independently H or C 1 -C 6 alkyl optionally substituted with F, OH, ONO, ONO 2 , COOH, C 1 -C 3 alkoxy or C 3 -C 6 cycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with R 15 ; 
         R 15  is C 1 -C 6 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, COOR 16 , NR 17 R 18 , CH═NR 19 , or with a tetrazole moiety which is optionally substituted with C 1 -C 3 alkyl; or a heteroaryl ring which is optionally substituted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen; 
         R 16  is H, or C 1 -C 4 alkyl optionally substituted with F, OH, ONO, ONO 2 , NR 17 R 18 , or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitrogen, wherein nitrogen atom is directly bound to C 1 -C 4  alkyl; 
         R 17  and R 18  are each independently H or C 1 -C 4 alkyl optionally substituted with ONO or ONO 2 ; and 
         R 19  is C 1 -C 4 alkyl optionally substituted with F, ONO or ONO 2 ; or C 3 -C 6 cycloalkyl. 
       
     
     
       2. The compound according to  claim 1 , wherein R 1  is C 1 -C 3 alkyl. 
     
     
       3. The compound according to  claim 1 , wherein R 2  is H or C 1 -C 3 alkyl optionally substituted with OH, ONO or ONO 2 ; or C(O)OH, C(O)OC 1 -C 3 alkyl, CHO, CN, CR 8 ═N—OR 9 , CR 8 ═N—NR 10 R 11 , CR 8 ═NR 12 , CR 8 ═N—ONO 2 , C 1 -C 3 alkoxy or C 1 -C 3 alkylene-Y, wherein Y is ONO, ONO 2 , CHO, CN, OH, OC(O)H, OC 1 -C 3 alkylene-C(O)OH, OC 1 -C 3 alkylene-C(O)N(R 6 )OR 7 , OC(O)—C 1 -C 3 alkyl, C(O)OC 1 -C 3 alkyl, C(O)N(R 6 )OR 7 , CR 8 ═N—OR 9 , CR 8 ═N—NR 10 R 11 , CR 8 ═NR 12  or CR 8 ═N—ONO 2 . 
     
     
       4. The compound according to  claim 1 , wherein R 3  is C 1 -C 4 alkyl optionally substituted with OH, ONO, ONO 2  or C 1 -C 3  alkoxy; or C 2 -C 4 alkenyl. 
     
     
       5. The compound according to  claim 1 , wherein R 4  is C 1 -C 4 alkyl optionally substituted with C 1 -C 3 alkoxy, F, ONO or ONO 2 ; or C 2 -C 4 alkenyl. 
     
     
       6. The compound according to  claim 1 , wherein R 13  and R 14  together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is selected from piperidine and piperazine, and wherein said heterocyclic ring is substituted with R 15 ; wherein R 15  is C 1 -C 4 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, COOR 16 , NR 17 R 18  or CH═NR 19 ; and wherein
 R 16  is H, or C 1 -C 4 alkyl optionally substituted with F, OH, ONO or ONO 2 ; 
 R 17  and R 18  are each independently H or C 1 -C 4 alkyl optionally substituted with ONO or ONO 2 ; and 
 R 19  is C 1 -C 4 alkyl optionally substituted with F, ONO or ONO 2 . 
 
     
     
       7. The compound according to  claim 1 , wherein said compound of formula I is a compound of formula I*, or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein at least one of R 1 , R 2 , R 3 , R 4 , or R 20  independently of each other comprises at least one ONO 2  or ONO moiety; 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , and R 4 , are as defined in  claim 1 ; and wherein 
         X is CR 21  or N; 
         R 20  is C 1 -C 4 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, COOR 25 , NR 26 R 27  or CH═NR 28 ; 
         R 21  is H or C 1 -C 4 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, COOR 25 , NR 26 R 27  or CH═NR 28 ; 
         R 25  is H, or C 1 -C 4 alkyl optionally substituted with F, OH, ONO or ONO 2 ; 
         R 26  and R 27  are each independently H or C 1 -C 4 alkyl optionally substituted with ONO or ONO 2 ; and 
         R 28  is C 1 -C 4 alkyl optionally substituted with F, ONO, ONO 2 . 
       
     
     
       8. The compound according to  claim 7 , wherein
 R 1  is C 1 -C 3 alkyl; 
 R 2  is H, C 1 -C 3 alkyl optionally substituted with OH, ONO or ONO 2 ; CHO, CN, CR 8 ═N—OR 9 , CR 8 ═N—NR 10 R 11 , C 1 -C 3 alkoxy or C 1 -C 3 alkylene-Y, wherein Y is ONO, ONO 2 , CHO, CN, OH, OC(O)H, C(O)OC 1 -C 3 alkyl, CR 8 ═N—OR 9 , CR 8 ═N—NR 10 R 11 , or CR 8 ═N—ONO 2 , wherein R 6  and R 8  are independently of each other H or CH 3 ; R 9  is H or C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, C 1 -C 3 alkoxy, OC(O)H or OC(O)—C 1 -C 3 alkyl; R 10  and R 11  are each independently H or C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 , CN, COOH, C 1 -C 3 alkoxy, OC(O)H or OC(O)—C 1 -C 3 alkyl; 
 R 3  is C 1 -C 4 alkyl optionally substituted with OH, ONO, ONO 2  or C 1 -C 3 alkoxy; 
 R 4  is C 1 -C 4 alkyl optionally substituted with C 1 -C 3 alkoxy, F, ONO or ONO 2 ; 
 R 20  is C 1 -C 4 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, COOR 25  or NR 26 R 27 ; 
 R 21  is H or C 1 -C 4 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, COOR 25  or NR 26 R 27 ; 
 wherein R 25  is H, or C 1 -C 4 alkyl optionally substituted with OH, ONO or ONO 2 ; and 
 R 26  and R 27  are each independently H or C 1 -C 4 alkyl optionally substituted with ONO or ONO 2 . 
 
     
     
       9. The compound according to  claim 7 , wherein
 R 1  is C 1 -C 2 alkyl; 
 R 2  is H, C 1 -C 3 alkyl optionally substituted with OH, ONO, ONO 2 ; CHO, CR 8 ═N—OR 9  or C 1 -C 3 alkoxy or C 1 -C 3 alkylene-Y, wherein Y is ONO, ONO 2 , CN, or CR 8 ═N—OR 9 , wherein R 8  is H or CH 3 ; R 9  is H or C 1 -C 3 alkyl optionally substituted with OH, ONO or ONO 2 ; 
 R 3  is C 2 -C 3 alkyl optionally substituted with OH, ONO or ONO 2 ; 
 R 4  is C 2 -C 3 alkyl optionally substituted with ONO or ONO 2 ; 
 R 20  is C 1 -C 3 alkyl substituted with one, two or three substituents selected from OH, ONO and ONO 2 ; and 
 R 21  is H or C 1 -C 3 alkyl substituted with one or two substituents selected from OH, ONO and ONO 2 . 
 
     
     
       10. The compound according to  claim 1 , wherein said compound of formula I is a compound of formula I**, or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein at least one of R 1 , R 2 , R 3 , R 4 , R 22 , R 23  or R 24  independently of each other comprises at least one ONO 2  or ONO moiety; 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , and R 4 , are as defined in  claim 1 ; and wherein 
         R 22  is H or C 1 -C 4 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, COOR 25 , NR 26 R 27  or CH═NR 28 ; 
         R 23  and R 24  are each independently C 1 -C 4 alkyl optionally substituted with halogen, OH, ONO, ONO 2 , C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, COOR 25 , NR 26 R 27  or CH═NR 28 ; 
         R 25  is H, or C 1 -C 4 alkyl optionally substituted with F, OH, ONO or ONO 2 ; 
         R 26  and R 27  are each independently H or C 1 -C 4 alkyl optionally substituted with ONO or ONO 2 ; and 
         R 28  is C 1 -C 4 alkyl optionally substituted with F, ONO or ONO 2 . 
       
     
     
       11. The compound according to  claim 10 , wherein said
 R 22  is C 1 -C 2 alkyl; and 
 R 23  and R 24  are each independently C 1 -C 3 alkyl substituted with OH, ONO or ONO 2 . 
 
     
     
       12. The compound according to  claim 1 , wherein said compound is selected from
 (E)-2-(4-((3-(5-ethyl-6-((hydroxyimino) methyl)-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl nitrate (1a); 
 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (1b); 
 (E)-2-(1-((3-(5-ethyl-6-((hydroxyimino) methyl)-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (1c); 
 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)propyl nitrate (1d); 
 (E)-3-(1-((3-(5-ethyl-6-((hydroxyimino) methyl)-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)propyl nitrate (1e); 
 2-(4-((3-(5-ethyl-6-formyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl nitrate (1f); 
 2-(1-((3-(5-ethyl-6-formyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (1g); 
 3-(1-((3-(5-ethyl-6-formyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)propyl nitrate (1h); 
 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl nitrate (1i); 
 (R)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (1k); 
 (S)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (1l); 
 ((2R,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diyl)bis(ethane-2,1-diyl) dinitrate (1m); 
 (1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidine-4,4-diyl)bis(ethane-2,1-diyl) dinitrate (1n); 
 ((2S,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diyl)bis(ethane-2,1-diyl) dinitrate (1o); 
 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl dinitrate (1p); 
 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)-2-hydroxypropane-1,3-diyl dinitrate (1q); 
 (E)-2-(1-((4-ethoxy-3-(6-((hydroxyimino) methyl)-5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (2a); 
 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl)sulfonyl)piperidin-4-yl)propyl nitrate (2b); 
 2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (2c); 
 2-(4-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl nitrate (2d); 
 2-(1-((4-ethoxy-3-(6-formyl-5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (2e); 
 (E)-3-(4-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl)sulfonyl)piperazin-1-yl)propyl nitrate (2f); 
 (E)-2-(4-((4-ethoxy-3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl nitrate (2g); 
 2-(1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (3a); 
 2-(4-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl nitrate (3b); 
 (E)-2-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (3c); 
 3-(4-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)propyl nitrate (3d); 
 (E)-2-(4-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl nitrate (3e); 
 (E)-3-(4-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)propyl nitrate (3f); 
 (R)-1-(1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (3g); 
 (S)-1-(1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (3h); 
 (1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidine-4,4-diyl)bis(methylene) dinitrate (3i); 
 (1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)methyl nitrate (3k); 
 (R)-2-hydroxy-2-(1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (3l); 
 2-hydroxy-1-(1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate isomer a (3m); 
 2-hydroxy-1-(1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate isomer b (3n); 
 (R,E)-1-(1-((3-(6-((hydroxyimino)methyl)-5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (3o); 
 (S)-1-(1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (3p); and 
 (S)-2-hydroxy-2-(1-((3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (3q). 
 
     
     
       13. A pharmaceutical composition comprising at least one of the compounds of formula I of  claim 1 , or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable excipient, adjuvant, or carrier. 
     
     
       14. A method of inhibiting PDE5 in a human or in a non-human mammal, wherein said method comprises administering an effective amount of the compound of formula I of  claim 1  to said human or said non-human mammal. 
     
     
       15. The method of  claim 14 , wherein said human or non-human mammal is suffering from a disease selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud's disease, male erectile dysfunction, priapism, female sexual dysfunction, hair loss, skin aging, vascular aging, pulmonary artery hypertension; livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, stable, unstable and variant (Prinzmetal) angina; hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, Idiopathic pulmonary fibrosis (IPF), peyronic's disease, glaucoma or a disease characterized by disorders of gut motility like irritable bowel syndrome, liver fibrosis, Alzheimer's disease and chronic heart failure. 
     
     
       16. The compound according to  claim 1 , wherein R 13  and R 14  together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and wherein said heterocyclic ring is optionally substituted with R 15 . 
     
     
       17. The compound according to  claim 1 , wherein said R 6  and R 8  are independently of each other H or CH 3 . 
     
     
       18. The compound according to  claim 10 , wherein said R 22  is methyl; and R 23  and R 24  are each independently C 1 -C 3  alkyl substituted with ONO or ONO 2 . 
     
     
       19. The method according to  claim 15 , wherein said disease is selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, systemic sclerosis (SSc), scleroderma, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction. 
     
     
       20. The method according to  claim 15 , wherein said disease is selected from pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabetic neuropathy and pressure ulcer.